The present invention is directed to methods of treating mammalian interstitial cystitis and/or urethral syndrome, two painful lower urinary tract disorders for which there is no adequate treatment currently available. The methods generally comprise the administration of a pharmaceutically effective amount of Nifedipine (C.sub.17 H.sub.18 N.sub.2 O.sub.3), a calcium channel antagonist which has been primarily used for the treatment of coronary artery disease and hypertension. Since Nifedipine provides effective relief with few side effects and is an oral medication that is well tolerated and relatively inexpensive, it is an attractive therapeutic agent for the treatment of these two painful voiding disorders.
More particularly, interstitial cystitial cystitis is a painful disease of the urinary bladder which is of unknown etiology and is most commonly seen in adult women. It is characterized by a number of urinary difficulties such as suprapubic pressure and pain with bladder filling, urinary frequency, nocturia, dysuria, urgency and irritative voiding asociated with morphological and histological changes in the bladder.
Urethral syndrome is a related painful voiding disorder of unknown etiology effecting women exhibiting many of the conditions set forth above. In this regard, while there are many similarities between the characteristics and conditions of these two voiding disorders, they exhibit a number of different characteristics. Specifically, interstitial cystitis is a condition consisting of a symptom complex with a specific voiding pattern (frequency, urgency, nocturia, lower abdomino-perineal pain and possibly dysuria), associated with glomerulations in response to bladder filling and, if present, a Hunner's ulcer. In contrast, patients with the urethral syndrome experience dysuria, urgency (usually with frequency) and sometimes abdominoperineal pain in the absence of nocturia and the cystoscopic findings consistent with interstitial cystitis.
As a result of the absence of a specific cause for, and unique histology of these disorders, no universally effective treatment processes or cures have been implemented. Along this line, there have been a multitude of proposed etiologies for interstitial cystitis, including the following: infection (Fall, M., Johansson, S. L. and Vahlne, A.: J. Urol., 133:771-5, 1985; Gillespie, L. M. and Jones, J. F.: J. Urol., 135:271A, 1986; and, Hunner, G. L.: Boston Med. Surg. J.,: 172:660-4, 1915), allergic or immune disorder (Oravisto, K. J.: Eur. Urol., 6:10-3, 1980; Gordon, H. L. Rosen, R. D., Hersh, E. M., and Yium, J. J.: J. Urol., 109:228-33, 1973; and, Matilla, J.: Clin. Immun. Immunopath., 23:81-9, 1982), defective transitional mucosa (Parsons, C. L., Boychuk, D., Jones, S., Hurst, R. and Callahan, H.: Invest. Urol., 143:139-42, 1990), endocrinologic disturbance (Powell, T. O.: Surq. Gynecol. Obstet., 78:605-9, 1944), toxic urinary chemicals (Clemensen, O., Lose, G., Holm-Bentzen, M. and Colstrup, H.: Urology, 2:17-20, 1988), psychiatric disorder (Blaivas, S. and Blaivas, J. G.: J. Urol., 135:189A, 1986), neurogenic disorder (Fall, M.: J. Urol., 133:774-8, 1985), lymphatic obstruction (Coutts, W. E. and Vargas-Zalazar, R.: Urol. Cut. Rev., 49:166-71, 1945) and vascular obstruction (Galloway, N. T. M., Gabale, B. R. and Irwin, P.: Semin, Urol., 1991, (in press)),
The current speculation regarding the cause of interstitial cystitis can be divided into two schools of thought: those who believe that the disease is caused primarily by a defect in the bladder mucosa, which may initiate an autoimmune response, and which may be exacerbated by the release of inflammatory mediators; and those who believe that the disease is a variant of reflex sympathetic dystrophy, an autonomic nerve-mediated ischemia known to affect limbs (Chuinard, R. G., Dabezies, E. J., Gould, J. S., Murphy, G. A. and Mathews, R. E.: South Med. J., 74:1481-4, 1981), in which a subtle ischemia of the bladder is responsible for the mucosal defects and for the associated inflammation.
Regardless of the cause of interstitial cystitis, several investigators have shown that the inflammatory symptoms of this disease are associated with an immune response. Gordan and associates (Gordon, H. L., Rossen, R. D., Hersh, E. M. and Yium, J. J.: J. Urol., 109:228-33, 1973) observed immunoglobulin deposits in the mucosal and submucosal layers of the bladder. Submucosal T-cell infiltrates were characterized by both Hanno and associates (Hanno, P., Levin, R. M., Monson, F. C., Teusher, C., Zhou, Z. Z., Ruggieri, M., Whitmore, K. and Wein, A. J.: J. Urol., 143:278-81, 1990), and Christmas and Associates (Christmas, T. J., Rode, J., Bothazzo, G. F. and Milroy, E. J. G.: Eur. Urol., 18:415-8, 1990). Witherow and associates (Witherow, R. O'N, Gillespie, L., McMullen, L., Goldin, R. D. and Walker, M. M.: Br. J. Urol., 64:158-67, 1989) described an humoral immune response associated with submucosal B-cell infiltrates. The historical failure of immunosuppressant (or anti-inflammatory) therapy (Hanno, P. M. and Wein, A. J.: Urology (suppl.), 29:22-26, 1987), however, suggests that interstitial cystitis is not primarily an autoimmune phenomenon.
Furthermore, some investigators have suggested that interstitial cystitis is a form of reflex sympathetic dystrophy (Galloway, N. T. M., Gabale, B. R. and Irwin, P.: "Interstitial Cystitis: A Form of Reflex Sympathetic Dystrophy?", Semin. Urol., (in press)), a syndrome characterized by end-organ (limb) ischemia and pain which progresses to atrophy, all of which is secondary to a dysfunctional sympathetic nervous system reflex loop. In theory, reflex sympathetic dystrophy of the bladder may be initiated by any shock or insult to the bladder (direct trauma, infection or dysfunctional voiding) followed by a sympathetic nervous system constriction of the arteries to the detrusor muscle; the ischemic insult is perpetuated by dysfunctional voiding, perhaps in response to the pain caused by ischemia, and the ultimate consequence of this vicious spiral is a pale, contracted bladder (end-stage disease).
However, the relationship between the detrusor muscle and the pathogenesis of interstitial cystitis (i.e. the reflex sympathetic dystrophy theory) has been controversial. Perez-Marrero and associates (PerezMarrero, R., Emerson, L. E. and Juma, S.: Urology (suppl.), 29:27-30, 1987) characterized 50 "interstitial cystitis" patients according to cystometric parameters: 13 of the 50 patients had uninhibited detrusor contractions, but no patient had a decrease in detrusor compliance. Contrary to these findings, the consensus report from the 1987 National Institutes of Health workshop (Gillenwater, J. Y. and Wein, A. J.: J. Urol., 140:203-6, 1988) declared that involuntary detrusor contractions excludes the diagnosis of interstitial cystitis, and a decreased bladder compliance is 1 of the 4 "positive factors" which are used in establishing the diagnosis (2 of 4 positive factors require). Additionally, it is well-established that the symptoms of interstitial cystitis cannot be relieved to the patient's satisfaction by administering anticholinergic agents (Messing, E. M: In Walsh, P. C., Gittes, R. F., Perlmutter, A. D., Stamey, T. A. (eds): Camobell's Urology., Philadelphia, W. B. Saunders Co., 1986, pp. 1070-86).
Calcium channel antagonists such as Verapamil, Diltiazem and Nifedipine inhibit intracellular shifts of calcium in a variety of cell types. As potent inhibitors of vascular smooth muscle contractions, calcium channel antagonists have been used primarily for the treatment of cardiovascular disorders such as hypertension and coronary artery disease (Stone, P. H., Antman, E. M., Mueller, J. E. and Braunwald, E.: Ann Int. Med., 93:886-904, 1980). In small clinical trials Nifedipine yielded mixed results for the treatment of esophageal spasms (Richter, J. E., Dalton, C. B., Bradley, L. A. and Castell, D. O.: Gastroent., 93:21-8, 1987) and for the relief of ureteral spasms (Viskin, S., Saver, I., Greenstein, A. and Hassner, A.: Ann Int. Med., 105:142, 1986). Under experimental conditions calcium channel antagonists are known to inhibit detrusor muscle (bladder) contractions more effectively than anticholinergic agents (Zar, M. A., Irivani, M. M. and Luheshi, G. N.: J. Urol., 143:835-9, 1990). Based on the results of these in vitro studies, a more efficient control of uninhibited detrusor contractions may have been possible by using a combination of anticholinergic and calcium channel blocking agents: both types of pharmacologic activities are present in Terodiline, but this drug had only limited clinical success in the treatment of patients with detrusor instability (Tapp, A., Fall, M., Norgaard, J., Massey, A., Choa, R., Carr, T., Korhonen, M. and Abrams, P.: U. Urol. 142:1027-31, 1989).
Calcium channel antagonists also affect the immune response by reducing the transport of calcium across lymphocyte cell membranes and by limiting the availability of calcium to immunoregulatory protein receptor sites. It has been shown that inhibition of the intracellular shift of calcium alone can suppress lymphocyte proliferation, even in the presence of lectins (Lindahl-Kisseling, K. M.: Exp. Cell Research, 103:151-7, 1976). Brix and associates (Brix, D. L., Berger, M. and Fleisher, T. A.: J. Immunol., 133:2904-9, 1984) observed that both the interactions of IL-2 with its receptor and IL-2 mediated T-cell proliferation can be inhibited by Diltiazem, Verapamil or Nifedipine. Of particular relevance to this proposal are the data reported by Corteza and associates (Corteza, O., Shen, S., Revie, D. and Chretien, P.: Transplant, 47:339-42, 1989), who demonstrated variable effects on delayed-type hypersensitivity by the three classes of calcium channel antagonists in C3H mice: Diltiazem had no significant influence, Nifedipine suppressed delayed-type hypersensitivity, but Verapamil enhanced this type of immune response. In the event that an immune response may be responsible, in part, for some of the symptoms of interstitial cystitis, the observations of Corteza and associates lend some support to the choice by the present invention of Nifedipine over other calcium channel antagonists for the treatment of interstitial cystitis.
Nifedipine, therefore, has three potential mechanisms for influencing the voiding symptoms in patients with interstitial cystitis: detrusor muscle relaxation, vascular smooth muscle relaxation or immunosuppression. In view of the fact that the patients who fulfill the NIH criteria (Gillenwater, J. Y. and Wein, A. J. J. Urol., 140:203-6, 1988) for this disease cannot have had a favorable response either to anti-spasmodic (bladder muscle relaxants) or to immunosuppressive agents alone (Messing, E. M.: in Walsh, P. C., Gittes, R. F., Perlmutter, A. D., Stamey, T. A. (eds): Campbell's Urology., Philadelphia, W. B. Saunders Co., 1986, pp. 1070-86; and, Hanno, P. H. and Wein, A. J.: J. Urol., 141:846-8, 1989), it was believed that Nifedipine would not have been a useful therapeutic agent for the treatment of interstitial cystitis and/or urethral syndrome.
However, as more clearly demonstrated below, Nifedipine has proven to be an effective therapeutic agent for the treatment of these two painful voiding disorders. While not wishing to be bound to any theory or mode of operation, it is the present inventor's opinion, which is not held widely by other urologists at this time, that interstitial cystitis is a variant of reflex sympathetic dystrophy, and that Nifedipine is effective, because it affects the vascular smooth muscle supply the bladder, and interrupts the abnormal reflex loop.
As a result, the present invention is directed to a new therapeutic process for treating mammalian interstitial cystitis and/or urethral syndrome. The objects and advantages of the present invention are more particularly set forth below.